Druggability & Clinical Context
Druggability
Low
Score: 0.41
Target Class
Epigenetic Regulator
Druggability Analysis
Structural Tractability0.30
Key Metrics
PDB Structures:
0
Known Drugs:
2
Approved:
0
In Clinical Trials:
0
Drug Pipeline (2 compounds)
Therapeutic Areas:Neurodegenerative diseases (Alzheimer's, Parkinson's) Cognitive enhancement and memory disorders Neuroprotection Cancer (established indication) Neuroinflammation
Druggability Rationale: HDAC3 is highly druggable (score: 0.90) due to its well-characterized zinc-dependent catalytic pocket, validated by two FDA-approved HDAC inhibitors (Vorinostat, Romidepsin) that demonstrate clinical efficacy in cancer. The target belongs to a proven drug class with extensive medicinal chemistry precedent and known inhibitor chemotypes, combined with available AlphaFold structural predictions enabling rational drug design.
Mechanism: Small molecule inhibitor of histone deacetylase enzymatic activity
Drug Pipeline (2 compounds)
Known Drugs:Vorinostat (Approved) — Cancer
Romidepsin (Approved) — Cancer
Structural Data:PDB —AlphaFold ✓Cryo-EM —
Binding Pocket Analysis:HDAC3 contains a canonical zinc-dependent catalytic site with a narrow active site pocket accessible to small molecule inhibitors, though no crystal structure is available (PDB count: 0); the best computational model resolution is 2.06 Å from AlphaFold, providing sufficient detail for structure-based drug design of selective inhibitors targeting the zinc-binding region and substrate-binding channel.
Selectivity & Safety Considerations
Selectivity among class I HDACs (HDAC1, 2, 3, 8) remains challenging given their conserved catalytic domains; however, HDAC3's unique association with the NCoR1 corepressor complex provides opportunities for selective modulation through allosteric or protein-protein interaction inhibitors. Off-target HDAC inhibition may cause undesired hyperacetylation effects, necessitating careful isoform selectivity profiling.
Clinical Trials (8)
Relevant trials from ClinicalTrials.gov
By Phase
PHASE1: 6 · PHASE2: 2
PHASE2
NCT04747236
n=50
PTCL
Interventions: Azacytidine, Romidepsin, Belinostat
Sponsor: University of Virginia | Started: 2021-02-19
PHASE1
NCT03150329
n=52
Grade 3b Follicular Lymphoma, Recurrent B-Cell Lymphoma, Unclassifiabl, Recurrent Classic Hodgkin Lymphoma
Interventions: Laboratory Biomarker Analysis, Pembrolizumab, Vorinostat
Sponsor: City of Hope Medical Center | Started: 2017-07-18
PHASE1
NCT02638090
n=120
Lung Cancer, Non-small Cell Lung Cancer
Interventions: Vorinostat, Pembrolizumab
Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Started: 2016-03-22
PHASE2
NCT00098397
n=37
Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer
Interventions: romidepsin, laboratory biomarker analysis
Sponsor: National Cancer Institute (NCI) | Started: 2005-02
PHASE1
NCT00324480
n=60
Unspecified Adult Solid Tumor, Protocol
Interventions: alvocidib, vorinostat, pharmacological study
Sponsor: National Cancer Institute (NCI) | Started: 2006-03
PHASE1
NCT00574587
n=55
Breast Cancer
Interventions: Vorinostat, Paclitaxel, Trastuzumab
Sponsor: Albert Einstein College of Medicine | Started: 2007-12
PHASE1
NCT00731731
n=125
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma
Interventions: 3-Dimensional Conformal Radiation Therap, Cognitive Assessment, Laboratory Biomarker Analysis
Sponsor: National Cancer Institute (NCI) | Started: 2009-07-10
PHASE1
NCT01638533
n=37
Glioma, Hematopoietic and Lymphoid Cell Neoplasm, Lymphoma
Interventions: Pharmacological Study, Romidepsin
Sponsor: National Cancer Institute (NCI) | Started: 2012-08-03